title: Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants.
abstract: Many lifespan-modulating genes are involved in either generation of oxidative substrates and end-products, or their detoxification and removal. Among such metabolites, only lipoperoxides have the ability to produce free-radical chain reactions. For this study, fatty-acid profiles were compared across a panel of C. elegans mutants that span a tenfold range of longevities in a uniform genetic background. Two lipid structural properties correlated extremely well with lifespan in these worms: fatty-acid chain length and susceptibility to oxidation both decreased sharply in the longest-lived mutants (affecting the insulinlike-signaling pathway). This suggested a functional model in which longevity benefits from a reduction in lipid peroxidation substrates, offset by a coordinate decline in fatty-acid chain length to maintain membrane fluidity. This model was tested by disrupting the underlying steps in lipid biosynthesis, using RNAi knockdown to deplete transcripts of genes involved in fatty-acid metabolism. These interventions produced effects on longevity that were fully consistent with the functions and abundances of their products. Most knockdowns also produced concordant effects on survival of hydrogen peroxide stress, which can trigger lipoperoxide chain reactions.
authors.affiliation: Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA. rjsr@uams.edu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Shmookler Reis
authors.forename: Lulu
authors.initials: L
authors.lastname: Xu
authors.forename: Hoonyong
authors.initials: H
authors.lastname: Lee
authors.forename: Minho
authors.initials: M
authors.lastname: Chae
authors.forename: John J
authors.initials: JJ
authors.lastname: Thaden
authors.forename: Puneet
authors.initials: P
authors.lastname: Bharill
authors.forename: Cagdas
authors.initials: C
authors.lastname: Tazearslan
authors.forename: Eric
authors.initials: E
authors.lastname: Siegel
authors.forename: Ramani
authors.initials: R
authors.lastname: Alla
authors.forename: Piotr
authors.initials: P
authors.lastname: Zimniak
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ayyadevara
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008055:Lipids / Q000096:biosynthesis*; D008136:Longevity / Q000502:physiology*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D034622:RNA Interference; D015996:Survival Rate; D014158:Transcription, Genetic
chemical_list: D029742:Caenorhabditis elegans Proteins; D005227:Fatty Acids; D008055:Lipids; D016877:Oxidants; D006861:Hydrogen Peroxide